The mitochondria-targeted antioxidant SkQ1 restores<b>α</b>B-crystallin expression and protects against AMD-like retinopathy in OXYS rats

Muraleva, Natalia A.; Kozhevnikova, Oyuna S.; Zhdankina, A. A.; Stefanova, Natalia A.; Карамышева, Т. В.; Фурсова, А. Ж.; Kolosova, N. G.

doi:10.4161/15384101.2014.958393

Cited by 27 publications

(23 citation statements)

References 41 publications

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“…As described earlier, absence of αB crystallin leads to significant attenuation of angiogenesis via modulation of VEGF in models of intraocular diseases [4]. In a recent study, Muraleva et al [90] demonstrated that senescence-accelerated OXYS rat model of dry AMD develop spontaneous retinopathy because of decreased expression of αB crystallin. These above findings support the conclusion that α-crystallins may be effective targets for disease therapy.…”

Section: α-Crystallin and Its Constitutive Peptides As Therapeutic Momentioning

confidence: 93%

Alpha crystallins in the retinal pigment epithelium and implications for the pathogenesis and treatment of age-related macular degeneration

Kannan

Sreekumar

Hinton

2016

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background αA- and αB crystallins are principal members of the small heat shock protein family and elicit both a cell protective function and a chaperone function. α-Crystallins have been found to be prominent proteins in normal and pathological retina emphasizing the importance for in-depth understanding of their function and significance. Scope of Review Retinal pigment epithelial cells (RPE) play a vital role in the pathogenesis of age-related macular degeneration (AMD). This review addresses a number of cellular functions mediated by α-crystallins in the retina. Prominent expression of αB crystallin in mitochondria may serve to protect cells from oxidative injury. αB crystallin as secretory protein via exosomes can offer neuroprotection to adjacent RPE cells and photoreceptors. The availability of chaperone-containing minipeptides of αB crystallin could prove to be a valuable new tool for therapeutic treatment of retinal disorders. Major Conclusions α-Crystallins are expressed in cytosol and mitochondria of RPE cells and are regulated during oxygen-induced retinopathy and during development. α-Crystallins protect RPE from oxidative-and ER stress-induced injury and autophagy. αB-Crystallin is a modulator of angiogenesis and vascular endothelial growth factor. αB Crystallin is secreted via exosomal pathway. Minichaperone peptides derived from αB Crystallin prevent oxidant induced cell death and have therapeutic potential. General Significance Overall, this review summarizes several novel properties of α-crystallins and their relevance to maintaining normal retinal function. In particular, the use of α-crystallin derived peptides is a promising therapeutic strategy to combat retinal diseases such as AMD.

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Section: α-Crystallin and Its Constitutive Peptides As Therapeutic Momentioning

confidence: 93%

Alpha crystallins in the retinal pigment epithelium and implications for the pathogenesis and treatment of age-related macular degeneration

Kannan

Sreekumar

Hinton

2016

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…There is evidence that a suitable experimental model of AMD is senescence-accelerated OXYS rats, which spontaneously develop a phenotype similar to human age-related disorders including AMD-like retinopathy [5][6][7][8][9][10][11]. Retinopathy that develops in OXYS rats already at a young age corresponds (in terms of clinical manifestations and morphological characteristics) to the dry atrophic form of AMD in humans.…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical localization of NGF, BDNF, and their receptors in a normal and AMD-like rat retina

2019

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Background: Age-related macular degeneration (AMD) is a major cause of blindness in developed countries, and the molecular pathogenesis of AMD is poorly understood. A large body of evidence has corroborated the key role of neurotrophins in development, proliferation, differentiation, and survival of retinal cells. Neurotrophin deprivation has been proposed to contribute to retinal-cell death associated with neurodegenerative diseases. Little is known about the expression of the immature form of neurotrophins (proneurotrophins) and their mature form [e.g., nerve growth factor (proNGF and mNGF) and brain-derived neurotrophic factor (proBDNF and mBDNF)] in the retina during physiological aging and against the background of AMD. In addition, cell-specific localization of proteins NGF and BDNF in the retina during AMD development is not clear. Here, we evaluated contributions of the age-related alterations in the neurotrophin system to the development of AMD-like retinopathy in OXYS rats. Methods: Male OXYS rats at preclinical (20 days), early (3 months), and late (18 months) stages of the disease and age-matched male Wistar rats (as controls) were used. We performed immunohistochemical localization of NGF, BDNF, and their receptors TrkA, TrkB, and p75NTR by fluorescence microscopy in retinal sections from OXYS and Wistar rats. Results: We found increased NGF staining in Muller cells in 18-month-old OXYS rats (progressive stage of retinopathy). In contrast, we observed only subtle changes in the labeling of mature BDNF (mBDNF) and TrkB during the development of AMD-like retinopathy in OXYS rats. Using colocalization with vimentin and NeuN, we detected a difference in the cell type-specific localization of mBDNF between OXYS and Wistar rats. We showed that the mBDNF protein was located in Muller cells in OXYS rats, whereas in the Wistar retina, mBDNF immunoreactivity was detected in Muller cells and ganglion cells. During the development of AMD-like retinopathy, proBDNF dominated over mBDNF during increasing cell loss in the OXYS retina. Conclusions: These data indicate that alterations in the balance of neurotrophic factors in the retina are involved in the development of AMD-like retinopathy in OXYS rats and confirm their participation in the pathogenesis of AMD in humans.

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“…Just as the dry form of human AMD, the initial alterations in the RPE cells later lead to atrophy of the choriocapillaris and the complete loss of photoreceptor cells in the OXYS rats' retinas by the age of 24 months. 12,14,15 Previously, by means of RNA sequencing (RNA-Seq), we determined that the retinopathy in OXYS rats at the first stage (age 3 months) and second stage (age 18 months) develops simultaneously with changes in mRNA levels of hundreds of genes. Most of them are linked to immune responses, inflammation, the response to oxidative stress, Ca 2C homeostasis, and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

“…[11][12][13][14][15][16] OXYS rats develop retinopathy similar to the dry form of human AMD according to the clinical signs, morphological features, and some molecular changes. In these rats, the clinical signs of retinopathy appear by the age of 3 months during a reduction in the transverse area of the RPE and impairment of choroidal microcirculation.…”

Section: Introductionmentioning

confidence: 99%

Identification of functional networks associated with cell death in the retina of OXYS rats during the development of retinopathy

et al. 2015

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Age-related macular degeneration (AMD) is a major cause of blindness in developed countries, and the molecular pathogenesis of early events in AMD is poorly understood. Senescence-accelerated OXYS rats develop AMD-like retinopathy. The aim of this study was to explore the differences in retinal gene expression between OXYS and Wistar (control) rats at age 20 d and to identify the pathways of retinal cell death involved in the OXYS retinopathy initiation and progression. Retinal mRNA profiles of 20-day-old OXYS and Wistar rats were generated at the sequencing read depth 40 mln, in triplicate, using Illumina GAIIx. A terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay was performed to measure the apoptosis level. GeneMANIA was used to construct interaction networks for differentially expressed (DE) apoptosis-related genes at ages 20 d and 3 and 18 months. Functional analysis was suggestive of a developmental process, signal transduction, and cell differentiation as the most enriched biological processes among 245 DE genes at age 20 d An increased level of apoptosis was observed in OXYS rats at age 20 d but not at advanced stages. We identified functional clusters in the constructed interaction networks and possible hub genes (Rasa1, cFLAR, Birc3, Cdk1, Hspa1b, Erbb3, and Ntf3). We also demonstrated the significance of the extrinsic apoptotic pathway at preclinical, early, and advanced stages of retinopathy development. Besides the cell death signaling pathways, immune system-related processes and lipid-metabolic processes showed overrepresentation in the clusters of all networks. These characteristics of the expression profile of the genes functionally associated with apoptosis may contribute to the pathogenesis of AMD-like retinopathy in senescence-accelerated OXYS rats.

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The mitochondria-targeted antioxidant SkQ1 restoresαB-crystallin expression and protects against AMD-like retinopathy in OXYS rats

Cited by 27 publications

References 41 publications

Alpha crystallins in the retinal pigment epithelium and implications for the pathogenesis and treatment of age-related macular degeneration

Alpha crystallins in the retinal pigment epithelium and implications for the pathogenesis and treatment of age-related macular degeneration

Immunohistochemical localization of NGF, BDNF, and their receptors in a normal and AMD-like rat retina

Identification of functional networks associated with cell death in the retina of OXYS rats during the development of retinopathy

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